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Overexpression of histone deacetylases (HDACs) are observed in different types of cancers, but histone deacetylase inhibitors (HDACIs) have not shown significant efficacy as monotherapy against solid tumors. Recently, studies demonstrated that it is promi

The N-arylation of chiral amino acid esters with minimal racemization is a challenging transformation because of the sensitivity of the α-stereocenter. A versatile synthetic method was developed to prepare N-arylated amino acid esters using cyclohexanones as aryl sources under continuous-flow conditions. The designed flow system, which consists of a coil reactor and a packed-bed reactor containing a Pd(OH)2/C catalyst, efficiently afforded the desired N-arylated amino acids without significant racemization, accompanied by only small amounts of easily removable co-products (i. e., H2O and alkanes). The efficiency and robustness of this method allowed for the continuous synthesis of the desired product in very high yield and enantiopurity with high space-time yield (74.1 g L?1 h?1) and turnover frequency (5.9 h?1) for at least 3 days.

A previous study for the identification of acetylcholinesterase (AChE) inhibitors demonstrated that the hybrid between tyrosol, the 1,2,3-triazole nucleus, and the coumarin group, namely 7-({1-[2-(4-hydroxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}methoxy)-4-methyl-2H-chromen-2-one (10), has a high enzyme inhibitory activity. Here, we synthesized analogues of 10 via triazole with pharmacophoric groups represented by tyrosine, phenylalanine, tryptophan, and glycine in addition to evaluating the impact of coumarin-linked amino acids on AChE inhibition. We obtained eight triazoles, six of which are undescribed. In general, the presence of carboxylic acid decreased the inhibitory activity, while aromatic amino acids increased enzymatic inhibition compared to glycine. The derivative containing tyrosine, structurally most similar to 10, presented the lowest inhibition percentage, indicating that phenolic hydroxyl is not the preponderant factor for inhibition. Molecular docking was not enough to explain in vitro experiments. On the other hand, MlogP (logP calculated by the Moriguchi method) was related positively to enzymatic inhibition. To increase the hydrophobicity of the molecules, we tested the esterified triazole derivatives comparatively with the enzyme. The compound ethyl 2-(4-(((4-methyl-2-oxo-2H-chromen-7-yl)oxy)methyl)- 1H-1,2,3-triazol-1-yl)acetate (6) presented an increment of inhibitory activity of 46.97 ± 1.75% at 100 μmol L-1. We also associated the best activity with the lowest van der Waals volume and molar mass values.

Leishmaniasis is one of today's most neglected diseases. The emergence of new anti-leishmanial therapies emphasizes several study groups funded by the World Health Organization. The present investigation will focus on the research to determine a few new potential derivatives of β-carboline ester derivatives against leishmaniasis. The in-silico predicted ADMET properties of most of the titled compounds are in an acceptable range and having drug like properties. Among all the tested analogs, compound ES-3 (EC50 3.36 μM; SI > 29.80) showed comparable and equipotent anti-leishmanial activity as that of standard drug miltefosine (EC50 4.80 μM; SI > 20.80) against amastigote forms of the tested L. infantum strain. Two compounds ES-6 and ES-10 exhibited significant activity with EC50 10.16, 13.56 μM; SI > 4.90, 7.37, respectively. In-silico based molecular docking and dynamics study of the significantly active analog also performed to study the putative binding mode, interaction pattern at the active site of the target leishmanial trypanothione reductase enzyme as well as stability of the target-ligand complex. The changes in the conformation of molecules during MD (frame wise trajectory analysis) provided new insights for the development of novel potent molecules. These findings will further give insight that will help modify the compound ES-3 for better potency and the design of novel inhibitors for leishmaniasis. Communicated by Ramaswamy H. Sarma.

The invention provides a DL-tryptophan compound represented by a general formula I or a pharmaceutically acceptable salt thereof, a preparation method and applications thereof, especially applicationsin preparation of RANKL inhibitors. According to the DL-tryptophan compound or the pharmaceutically acceptable salt thereof, an OPG-RANKL-RANK signal system can be intervened by inhibiting the interaction of RANKL-RANK, and the activity of RANKL in osteoclast precursor cells is regulated and controlled, so that formation of osteoclasts is inhibited, and bone resorption is reduced; and the DL-tryptophan compound or the pharmaceutically acceptable salt thereof is expected to play a role in preventing and treating bone metabolic diseases, and brings good news to bone metabolic disease patients.

In this paper, we describe the solvent-free three-component synthesis of 2,4,5-trisubstituted-1H-pyrrol-3-ol-type compounds from L-tryptophan. The first step of the synthetic methodology involved the esterification of L-tryptophan in excellent yields (93–98%). Equimolar mixtures of alkyl 2-aminoesters, 1,3-dicarbonyl compounds, and potassium hydroxide (0.1 eq.) were heated under solvent-free conditions. The title compounds were obtained in moderate to good yields (45%–81%). Density functional theory using “Becke, 3-parameter, Lee–Yang–Parr” correlational functional (DFT-B3LYP) calculations were performed to understand the molecular stability of the synthesized compounds and the tautomeric equilibrium from 3H-pyrrol-3-one type intermediates to 1H-pyrrol-3-ol type aromatized rings.

A facile transformation of 1-formyl β-carboline into fluorescent β-carboline C-1 tethered benzazole derivatives is described under the catalysis of ZnO nanoparticles. The reaction proceeded with the reaction of 1-formyl β-carboline and substituted o-diaminobenzene/2-aminobenzenethiol/2-aminophenol, which results in formation of a Schiff base, followed by an intramolecular cylization reaction to generate β-carboline linked benzimidazole, benzothiazole and benzoxazole derivatives. This appraoch displayed a wide substrate scope and high regioselectivity to yield the desired products in moderate to good yields. The photophysical properties of the synthesized derivatives were also evaluated and they exhibited excellent fluorescence properties. Among these β-carboline substituted azoles, the benzothiazole derivative displayed the maximum quantum yield (ΦF up to 28%).

Targeting RANKL/RANK offers the possibility of developing novel therapeutic approaches to treat bone metabolic diseases. Multiple efforts have been made to inhibit RANKL. For example, marketed monoclonal antibody drug Denosumab could inhibit the maturation of osteoclasts by binding to RANKL. This study is an original approach aimed at discovering small-molecule inhibitors impeding RANKL/RANK protein interaction. We identified compound 34 as a potent and selective RANKL/RANK inhibitor by performing structure-based virtual screening and hit optimization. Disruption of the RANKL/RANK interaction by 34 effectively inhibits RANKL-induced osteoclastogenesis and bone resorption. The expression of osteoclast marker genes was also suppressed by treatment of 34. Furthermore, 34 markedly blocked the NFATc1/c-fos pathway. Thus, our current work demonstrates that the chemical tractability of the difficult PPI (RANKL/RANK) target by a small-molecule compound 34 offers a potential lead compound to facilitate the development of new medications for bone-related diseases.

A series of piperazinyl-β-carboline-3-carboxamide derivatives were designed through a molecular hybridization approach. Designed analogues were synthesized, characterized and evaluated for anti-leishmanial activity against Leishmania infantum and Leishmania donovani. In L. infantum inhibition assay, compounds 7d, 7g and 7c displayed potent inhibition of promastigotes (EC50 1.59, 1.47 and 3.73 μM respectively) and amastigotes (EC50 1.4, 1.9 and 2.6 μM respectively). SAR studies revealed that, para substitution of methoxy, chloro groups and methyl group on ortho position favored anti-leishmanial activity against L. infantum. Among these analogues 7d, 7h, 7n and 7g exhibited potent inhibition against L. donovani promastigotes (EC50 0.91, 4.0, 4.57 and 5.02 μM respectively), axenic amastigotes (EC50 0.9, 3.5, 2.2 and 3.8 μM respectively) and intracellular amastigotes (EC50 1.3, 7.8, 5.6 and 6.3 μM respectively). SAR studies suggested that, para substitution of methoxy group, para and meta substitution of chloro groups and benzyl replacement recommended for significant anti-leishmanial against L. donovani.

Molecular hybridization is a ligand based drug design approach is well known recent medicinal chemistry to design anti-parasitic agents. In the present study, we have designed a series of (1-phenyl-9H-pyrido [3,4-b]indol-3-yl) (4-phenylpiperazin-1-yl)methanone derivatives using molecular hybridization approach. Designed analogues were evaluated for cytotoxicity and inhibition activity against Leishmania infantum and Leishmania donovani. Among these reported analogues 7b, 7d, 7e, 7f and 7m displayed potent inhibition of both L. infantum and L. donovani. Compounds 7i and 7k exhibited selective potent inhibition of L. donovani. Especially, compounds 7e and 7k showed most potent anti-leishmanial activity against L. infantum and L. donovani respectively. Anti-leishmanial activity of these compounds is comparable with standard drugs miltefosine and pentamidine. SAR studies revealed that, electron donating group substitution on phenyl ring recommended for potent anti-leishmanial activity.

The present invention relates to certain bis-heteroaryl compounds, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia, fronto-temporal dementia, Huntington's Disease, amyotrophic lateral sclerosis, and multiple system atrophy, and cancer including melanoma.

A Pd/C-catalyzed cascade approach for the synthesis of attractive benzo-fused tropanes was developed. The reaction proceeds through a sequential Pd/C-catalyzed dehydrogenative formation of azomethine ylides from amines and 1,3-dipolar cycloaddition. It allows the generation of structurally complex benzo-fused tropanes in good yields with excellent diastereoselectivities under mild reaction conditions. Preliminary results of asymmetric version of the reaction reveal that the copper catalyst and chiral monophosphoramidite ligand can furnish optically active products with moderate ee.

The invention discloses a beta-carboline derivative or medicinal salt of a general formula (I) structure with anti-tumour activity, wherein R, R1 and R2 are defined in the specification.

The invention relates to a tryptophan derivative (I), a preparing method of the tryptophan derivative (I), and application of the tryptophan derivative (I) in preventing and treating plant viruses, killing bacteria and killing insects. The formula of the tryptophan derivative (I) is shown in the description, and the meanings of all groups in the formula are shown in the description. The tryptophan derivative expresses especially excellent plant virus resisting activity, and also has broad-spectrum bactericidal activity and insecticidal activity.

The present invention relates to β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives (I) and a method for preparing same and the use in the aspects of preventing and treating plant viruses, fungicides and insecticides. For the meaning of each group in formula (I) see the description. The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives of the present invention show a particularly ourstanding anti-plant virus activity, and also have fungicidal and insecticidal activities.

A direct C-2 methylation reaction of indoles bearing a readily removable N-2-pyrimidyl moiety as a site-specific directing group has been developed with a palladium catalyst. This reaction relied on the use of KF to promote efficient methylation. A moderate to good yield was achieved in a range of indole substrates.

According to our previous work and the latest research on the biosynthesis of β-carboline, and using the reverse thinking strategy, tryptophan, the biosynthesis precursor of β-carboline alkaloids, and their derivatives were synthesized, and their biological activities and structure-activity relationships were studied. This bioassay showed that these compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV); especially (S)-2-amino-3-(1H-indol-3-yl)-N-octylpropanamide (4) (63.3 ± 2.1%, 67.1 ± 1.9%, 68.7 ± 1.3%, and 64.5 ± 3.1%, 500 μg/mL) exhibited the best antiviral activity both in vitro and in vivo. Compound 4 was chosen for the field trials and the acute oral toxicity test, the results showed that the compound exhibited good anti-TMV activity in the field and low acute oral toxicity. We also found that these compounds showed antifungal activities and insecticidal activities.

An efficient methodology to obtain novel antifungal analogs of brassinin 1 is described. Starting from L-Tryptophan 2, N,N0-dialkylthiourea 4, 4-[(1H-indol-3-yl)methylene]-2-sulfanylidene- 1,3-Thiazolidin-5-one 5 and alkyl (2S)-3-(1H-indol-3-yl)-2-{[(alkylsulfanyl)carbonothioyl]amino} propanoate 6 type compounds were obtained as main products in different ratios depending on the reaction conditions via a tandem dithiocarbamate formation and Michael addition reaction. In order to understand the dependence of the reaction conditions on the mechanism pathway, a DFT/B3LYP study was performed. The results suggested the existence of competitive mechanistic routes which involve the presence of an ionic dithiocarbamate intermediate 9. Antifungal activities of all products were then evaluated against Fusarium oxysporum through mycelial growth inhibition using a microscale amended-medium assay. IC50 values were thus determined for each compound. These results showed that 6-related compounds can be considered as promissory antifungal agents.

In the present study, a new series of β-carboline derivatives were synthesized and evaluated for inhibition activity against both HIV-1 and HIV-2 strains. Among these reported analogues, surprisingly (1-phenyl-9H-pyrido[3,4-b]indol-3-yl)(4-p-tolylpiperazin-1-yl)methanone (7b), (4-(2-methoxyphenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7f), (4-(4-fluorophenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7k), (4-(2-fluorophenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7l) displayed selective inhibition of HIV-2 strain with EC50 values of 3.3, 3.2, 2.6 and 5.4 μM, respectively, which are comparable with nucleoside reverse transcriptase inhibitors lamivudine and dideoxyinosine. As these analogues have not shown in vitro HIV-2 reverse transcriptase inhibition, it could be excluded as potential target for their specific anti-HIV-2 activity.

A novel series of 1-(thiophen-2-yl)-9H-pyrido [3,4-b]indole derivatives were synthesized using DL-tryptophan as starting material. All the compounds were characterized by spectral analysis such as 1H NMR, Mass, IR, elemental analysis and evalua

Molecular hybridization is an emerging approach to design novel ligands by combination of two or more pharmacophoric subunits of known bioactive compounds. In the present study, we have designed a novel series of diarylpiperazine analogues, synthesized, characterized using FTIR, 1H NMR, Mass, Elemental analysis and evaluated their in-vitro anti-tubercular activity. Among the reported sixteen diarylpiperazines, eleven analogues exhibited significant anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain with MIC values below 6.25 μg/mL and good selectivity index. Structure activity relationship studies concluded that, ortho-para directing group (except para chloro) substitution on ortho and para position of piperazine attached phenyl ring favored anti-tubercular activity.

By drawing the creation ideas of botanical pesticides, a series of tetrahydro-β-carboline-3-carboxylic acid derivatives were designed and synthesized, and first evaluated for their anti-TMV, fungicidal and insecticidal activities. Most of these derivatives exhibited good antiviral activity against TMV both in vitro and in vivo. Especially, the activities of compounds 8 and 15 in vivo were higher than that of ribavirin. The compound 8 exhibited more than 70% fungicidal activities against Cercospora arachidicola Hori, Alternaria solani, Bipolaris maydis, and Rhizoctonia solani at 50 mg/kg, compounds 16 and 20 exhibited more than 60% insecticidal activities against Mythimna separate and Ostrinia nubilalis.

A total of 29 novel sulfenamide compounds were synthesized, spectroscopically characterized and evaluated in vitro for antimicrobial activity against various infectious pathogens. Compounds 1b and 2c exhibited potent inhibition against clinical Methicillin-resistant Staphylococcus aureus (MRSA) strains with minimum inhibitory concentration (MIC) values of 1.56 μg/mL.

Figure presented It is well-known that Nb-benzyltryptophan alkyl esters undergo the Pictet-Spengler reaction with aldehydes to furnish both cis- and trans-1,2,3,4-tetrahydro-β-carbolines, with the trans isomer predominating. Epimerization at C-1 took place under acidic conditions to produce, exclusively, the thermodynamically more stable trans diastereomer via internal asymmetric induction. Recent kinetic experiments provided insight into the cis to trans epimerization mechanism involved in the Pictet-Spengler reaction of 1,2,3-trisubsituted tetrahydro-β-carbolines. Since the epimerization reaction had been shown to be sensitive to electronic effects at C-1, the rate data for a series of 1-phenyl-substituted 1,2,3,4-tetrahydro- β-carbolines was investigated via a Hammett study. Analysis of the data supported the presence of a positively charged intermediate with a φ value of -1.4, although the existence of an iminium ion intermediate or a carbocationic intermediate could not be determined from this data alone. Analysis of the rate of epimerization demonstrated first-order kinetics with respect to TFA following the initial protonation of the substrate. This observation was consistent with the formation of a doubly protonated intermediate as the rate-determining step in the carbocation-mediated cis to trans epimerization process. In addition, the observed first-order rate dependence was inconsistent with the retro-Pictet-Spengler mechanism since protonation at the indole-2 position was not rate determining as demonstrated by kinetic isotope effects. Based on this kinetic data, the retro-Pictet-Spengler pathway was ruled out for the cis to trans epimerization of 1,2,3-trisubstituted 1,2,3,4-tetrahydro-β-carbolines, while the olefinic mechanism had been ruled out by experiments carried out in TFA-d.

Whole cells of Candida parapsilosis ATCC 7330 were used for the resolution of N-acetyl amino acid esters. Excellent enantioselectivities (E = 40 to >500) were achieved for the resolution of N-protected protein and non-protein amino acid esters giving good yields (28-50%) and high enantiomeric excesses (up to >99%) for both enantiomers.

The present study was undertaken to shed light on the mechanism of the epimerization of cis-1,2,3-trisubstituted tetrahydro-β-carbolines into the trans isomers via a potential carbocationic intermediate at C(1). In order to study the pathway involved in C

Lavendamycin analogues, methods for their synthesis, and methods for their use in the treatment of diseases such as cancer and HIV infection are described.

The preparation of a phosphoramidon precursor is described using a phosphorus(III) coupling protocol.

A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Schoellkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Schoellkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product total synthesis would originate from the inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-D-tryptophan 62 was prepared by this protocol on a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total synthesis of tryprostatin A (9a) was accomplished in 43% overall yield employing this palladium-mediated process.

Catalytic-transfer hydrogenation in iso-propanol under microwave irradiation has been performed to rapidly deprotect N-Cbz and N-Bn derivatives. The method is particularly suitable for the synthesis of short peptides and can also be carried out on supported molecules. The rapid cleavage of chiral molecules derived from (S)-1-phenylethylamine can be very useful for asymmetric synthesis of nitrogen containing compounds.

Products of formula (I), wherein n is 0 or 1, R1 is particularly phenyl or biphenyl optionally substituted particularly by benzyloxy, dioxol or halogen, R2 is particularly hydrogen or methyl substituted particularly by indolyl, phenylthio or phenyl, which may in turn be substituted, and A is carboxy, tetrazolyl or substituted alkyl as well as all salts and isomers thereof, are disclosed. STR1

A concise synthesis of optically active tryptophan derivatives was developed via diastereoselective alkylation of the Schollkopf chiral auxiliary 4 to provide alkyne 2 which underwent palladium-catalyzed heteroannulation with iodoanilines 1 to furnish protected tryptophans 3. Hydrolysis and subsequent saponification of 3 provided the desired tryptophans 12 in good yields.